1. Field of the Invention
This invention relates to canfosfamide and its salts, and in particular to their preparation and intermediates in their preparation.
2. Description of the Related Art
U.S. Pat. No. 5,556,942 and PCT International Publication No. WO 95/09866 disclose compounds of the formula
and their amides, esters, and salts, where:    L is an electron withdrawing leaving group;    Sx is —S(═O)—, —S(═O)2—, —S(═NH)—, —S(═O)(═NH)—, —S+(C1-C6 alkyl)-, —Se(═O)—, —Se(═O)2—, —Se(═NH)—, or —Se(═O)(═NH)—, or is —O—C(═O)—, or —HN—C(═O)—;    each R1, R2 and R3 is independently H or a non-interfering substituent;    n is 0, 1 or 2;    Y is selected from the group consisting of
where m is 1 or 2; and    AAc is an amino acid linked through a peptide bond to the remainder of the compound, and their syntheses.
The compounds are stated to be useful drugs for the selective treatment of target tissues that contain compatible GST isoenzymes, and simultaneously elevate the levels of GM progenitor cells in bone marrow. Disclosed embodiments for L include those that generate a drug that is cytotoxic to unwanted cells, including the phosphoramidate and phosphorodiamidate mustards.
TLK286, identified in those publications as TER 286 and named as γ-glutamyl-α-amino-β-((2-ethyl-N,N,N,N-tetra(2′-chloro)ethylphosphoramidate)sulfonyl)propionyl-(R)- (-)phenylglycine, is one of these compounds. TLK286 is the compound of the formula
TLK286 as the hydrochloride salt has the United States Adopted Name (USAN) of canfosfamide hydrochloride.
Lyttle et al., J. Med. Chem., 37:1501-1507 (1994), disclose canfosfamide and two analogs, their synthesis, and their interaction with three GST isoenzymes. The synthesis involves the reaction of the unprotected tripeptide (L-γ-glutamyl-L-cysteinyl-2-phenyl-(2R)-glycine in the case of canfosfamide) with a 2-bromoethyl phosphorodiamidate (2-bromoethyl N,N,N′,N′-tetrakis(2-chloroethyl)phosphorodiamidate in the case of canfosfamide), followed by oxidation of the resulting thioether with hydrogen peroxide and peracetic acid.
Canfosfamide is an anticancer compound that is activated by the actions of GST P1-1, and by GST A1-1, to release the cytotoxic phosphorodiamidate moiety. Following activation of canfosfamide by GST P1-1, apoptosis is induced through the stress response signaling pathway with the activation of MKK4, JNK, p38 MAP kinase, and caspase 3. In vitro, canfosfamide has been shown to be more potent in the M6709 human colon carcinoma cell line selected for resistance to doxorubicin and the MCF-7 human breast carcinoma cell line selected for resistance to cyclophosphamide, both of which overexpress GST P1-1, than in their parental cell lines; and in murine xenografts of M7609 engineered to have high, medium, and low levels of GST P1-1, the potency of canfosfamide was positively correlated with the level of GST P1-1 (Morgan et al., Cancer Res., 58:2568-2575 (1998)).
Canfosfamide hydrochloride, as a single agent, and in combination with other anticancer agents, is currently being evaluated in multiple clinical trials for the treatment of ovarian, breast, non-small cell lung, and colorectal cancers. It has demonstrated significant single agent antitumor activity and improvement in survival in patients with non-small cell lung cancer and ovarian cancer, and single agent antitumor activity in colorectal and breast cancer. Evidence from in vitro cell culture and tumor biopsies indicates that canfosfamide is non-cross-resistant to platinum, paclitaxel, and doxorubicin (Rosario et al., Mol. Pharmacol., 58:167-174 (2000)), and also to gemcitabine. Patients treated with canfosfamide hydrochloride show a very low incidence of clinically significant hematological toxicity.
Herr et al., Org. Proc. Res. Dev., 5:442-444 (2001), disclose a retrosynthetic approach to canfosfamide from the unprotected tripeptide L-γ-glutamyl-L-cysteinyl-2-phenyl-(2R)-glycine and a 2-(arylsulfonyloxy)ethyl N,N,N′,N′-tetrakis(2-chloroethyl)phosphorodiamidate; and the synthesis of the 2-(arylsulfonyloxy)ethyl N,N,N′,N′-tetrakis(2-chloroethyl)phosphorodiamidate in three steps from POCl3, passing through 2-hydroxyethyl N,N,N′,N′-tetrakis(2-chloroethyl)phosphorodiamidate. U.S. Pat. No. 6,506,739 and PCT International Publication No. WO 01/83496 disclose 2-(substituted)ethyl N,N,N′,N′-tetrakis(2-haloethyl)phosphorodiamidates, including 2-hydroxyethyl N,N,N′,N′-tetrakis(2-chloroethyl)phosphorodiamidate and 2-(arylsulfonylox)ethyl N,N,N′,N′-tetrakis(2-chloroethyl)phosphorodiamidates, such as 2-(4-bromobenzenesulfonyloxy)ethyl N,N,N′,N′-tetrakis (2-chloroethyl)phosphorodiamidate.
The disclosures of the documents referred to in this application are incorporated into this application by reference.